This research proposal is concerned with comparative studies of the major histocompatibility complex (MHC) in inbred and wild Norway rat populations. We have previously demonstrated that the genetic loci in the RTl complex that control the expression of serologically-defined histocompatibility and Ia antigens, the mixed lymphocyte response, and the immune response to synthetic polypeptide antigens are much less polymorphic than expected. In addition, these different loci in random populations exhibit high degrees of linkage disequilibrium, suggesting that selective pressures are preferentially influencing the retention of selected MHC haplotypes. The major emphasis of the experimental work of this grant application will focus on three areas. The first is a continued examination of the genetic fine structure of the MHC, particularly with regard to identifying and isolating new wild haplotypes that may allow identification of new loci within the complex. The second is the investigation of wild MHC haplotypes with genetic variation in the RT1.B region in an attempt to establish the genetic and functional relationships between the loci that code for the expression of Ia antigens, the mixed lymphocyte response and the immune response to simple antigens. The third area of investigation will be to establish the genetic control and expression of cell surface antigens that function as targets for the cell-mediated lympholysis reaction. Once identified, the influence of these antigens on the success or failure of kidney allografts exchanged between inbred and wild lines will be examined. The ability to detect specific components of the MHC in individual wild rats provides the opportunity to compare simultaneously inbred and wild populations of rats, allowing for the generation of natural genetic recombinations within the MHC and examination of how this important complex behaves under natural conditions.